Your Eyes and Chronic Graft versus Host Disease

Presenters:   ​Sandeep Jain, MD, University of Illinois Dry Eye and Ocular GVHD Clinic, ​Sunita Nathan, MD, Rush University Medical Center 

This is a recording of a workshop presented at the 2019 GVHD Summit. 

Presentation is 32 minutes, followed by 24 minutes of Q&A. 

Summary: 

Eyes can be damaged by graft-versus-host disease (GVHD). Treatment options depend on symptoms, but most long-term effects are preventable.

Highlights

• To prevent long-term damage to your eyes, see an ophthalmologist as soon as symptoms of GVHD in the eyes (ocular GVHD) occurs
• Ocular GVHD typically begins 7 months to 2 years after transplant, but the damage can last much longer.
• Treatments using aggressive therapies first, and then stepping down to less aggressive therapies, have been shown to be most effective in treating ocular GVHD

Key Points

05:27     Symptoms of ocular GVHD include red, irritated eyes; mucus discharge from the eye; light sensitivity; eye discomfort; and/or reduced vision.

06:10     Reporting symptoms of ocular GVHD early is critical. There is only a small window of opportunity to aggressively treat ocular GVHD for maximum success.

08: 35    GVHD can damage the eye’s lacrimal gland, preventing the production of tears and causing dryness.

12:12     Ocular GVHD is not just another dry eye problem and requires different treatment than other types of dry eye problems.

14: 23    Scarring under the eyelid is typical and can cause pain.

15: 36    Oil glands can be destroyed causing tears to evaporate.

17: 45    If you have ocular GVHD, it is important to use only preservative-free eye drops. Eye drops that contain preservatives can make the problem worse.

21: 53    Serum tears, made from the patient's own blood, can help relieve pain caused by ocular GVHD

23: 59    Special contact lens designed to relieve the pain of ocular GVHD are available

31:32     Although ocular GVHD can impair vision, if treated properly it does not cause blindness.

Transcript of Presentation 

00:00 [Moderator] Introduction of Speakers: Good morning, everyone, so my name is Kim Langer, and I'll be the moderator this morning. I'm looking forward to hearing from our guest speakers about this important topic. This session is designed to be interactive, but we do ask that you hold your questions until the end. We'll have a certain session for Q&A. It is my pleasure to introduce to you Dr. Sandeep Jain and Dr. Sunita Nathan.

Dr. Jain is the director of the Dry Eye and Ocular GVHD Clinic at the University of Illinois at Chicago, where he directs the Translational Biology Laboratory in the department of ophthalmology. He is the founding program director of the National Eye Institute, the National Institutes of Health-funded chronic GVHD meeting in Chicago, which focuses on the intersection between the areas of chronic GVHD and dry eyes/ocular surface disease.

Dr. Nathan is an associate professor of medicine and associate director of the division of hematology and the director of the quality program in the oncology and cell therapy section of BMT and cellular therapy at Rush Medical College in Chicago.

Please join me in welcoming Dr. Jain.

01:08 [Jain] Thank you very much. I really want to thank BMTInfoNet also to organize this very special meeting, and they're doing such a wonderful job in getting people to come together to think about this condition that develops which really affects the quality of life of patients. It affects many parts part of the body, and the eyes is one of them, and we're going to be talking about the eye today and how graft-versus-host disease affects the eye.

It is in fact, the eye problems are in fact one of the most common complications that happen after bone marrow transplant and, perhaps, affect the quality of life of patients after bone marrow transplant in a very significant way, because you need to see to be able to do anything, whether it's working on your iPhones or your computer. So even going outside without light sensitivity bothering you or just the pain and discomfort that can come from... come if the eyes get involved.

02:31     The way I want to think about this presentation is to ask a few questions and see what the answers to them would be, and these are just a few very basic questions that we'll be looking at. And I would encourage everybody to think about questions that you can ask me either after the presentation, but be free to interrupt during the presentation as well. I want this to be interactive. There is no point on me lecturing. I'm here to answer questions, and the best information is the information that you seek, not the information that I want to tell. That may just go over you and you may ignore it. It's maybe important for me, but maybe not important for you. So we'll try to keep this... so I'm going to deviate a little bit from what the program structure is to say that ask questions if you have one.

03:36     I've already been introduced. I am the director of the UIC ocular GVHD Clinic. We've linked our laboratory with their clinic, and this system has allowed us to generate new ideas, new data about the disease, why it happens and new therapeutics. We'll talk about some of that today.

04:40     Frequently asked questions about ocular GVHD:  So these the type of questions that I was talking about. What is ocular GVHD, and that's something very basic. Do I have eye GVHD? Is it just another form of dry eye? How do you treat it? Will I go blind from it? Do I have to use eye drops forever? Are there any new treatments that can help me? These are some of the questions that are there, just a few, and, of course, there are many more that stem from this questions, so what is ocular GVHD?

04:42     What is Ocular GVHD: Ocular GVHD is a severe inflammation of the surface of the eye that develops after bone marrow transplant. In general, we see the highest risk to be between about seven to nine months. That's where it starts till about two years. That time period is the time period when one is at greatest risk for developing ocular GVHD.  It presents as a red, irritated eye. There could be mucus discharge from the eye. There could be light sensitivity. It's just uncomfortable, and sometimes the vision is also reduced, so it is a symptomatic red eye that develops.

05:27     Symptoms of ocular GVHD:  Now, the most important thing in this slide or at this point is to understand that one should not ignore the initial symptoms as they develop. The moment the eye starts acting up, there is either redness or mucus discharge or there is discomfort or light sensitivity, one needs to be examined right away by an ophthalmologist and not just go to the drugstore to get artificial tears and ride it out or use Restasis or things like that, to think that we should treat it as just another dry eye. We'll talk about that more.

6:10  Reporting symptoms of ocular GVHD immediately is critical:  Why? Because there is only a small window of opportunity in which we can aggressively control inflammation as it is developing to get best outcomes.

If we allow the inflammation to develop before going to the aggressive treatments that we'll talk about, then it may already be too late. The tear production may already have gone down. The lacrimal gland, which produces tears, may already have lost its ability to produce tears. The surface of the eye may have already had scarring complications and inflammation may have already caused a lot of damage, so you don't want that happen, and that's what is I think the number message of this talk, that the moment the eye symptoms develop, you need to go to someone who has treated this condition.

Ideally, one should go before transplant for a baseline exam and then... so that one can figure out if there is any change. So this is what ocular GVHD is, a severe inflammation of the surface of the eye that can development after bone marrow transplant usually between seven to two years after the transplant.

07:26     Evaluation for Ocular GVHD:  Do I have ocular GVHD? That's the other question. We as a group, me and several other individuals from all over the world got together about five or six years ago to develop a classification system that takes four... three clinical signs and one symptom into consideration to diagnose ocular GVHD in a more formal fashion. And we give numbers to everything, numbers to a patient's misery, by doing symptom analysis, stain the surface of the cornea with dyes to see how much the surface disease is, dryness is, see how red the eye is and measure the tear production. And all of this we put some numbers on it to tally up the numbers in the end to see whether they rise above the level where we can diagnose the patient as having ocular GVHD or not.

8:30        Measuring tear production:  So, one of the things we do, we measure the tear production. Why? Because, in ocular GVHD, the ability to produce tears becomes... is lost because of damage to the lacrimal gland. The lacrimal gland sits over here. It produces tears, and they're very important for the eye health. If you don't produce tears, the eye will be dry, the surface will become diseased, and it will be... The eye will become red, irritated, and it could be very uncomfortable. So the second thing that we do is to see how much surface disease there is, what is the... how much dryness there is, what has the damage to the surface cells been caused by the dryness?

09:17     Test for Damaged Surface Membranes:  Now, once the eyes dry, the cells that line the surface of the eye, their membranes become damaged. Once their membranes become damaged, if we put a dye on the surface, it's a blue dye called lissamine or fluorescein, it can enter the cell. Normally, it won't enter the cells. If the cells are healthy, the dye is not going to go inside the cell, but if the membranes are damaged because of dryness, because of ocular GVHD, the dye will enter the cells, and we'll see those cells as spots, whether it is fluorescent spot with fluorescein or a green or a blue spot with lissamine green dye, and this is what this slide shows.

This is another slide to show you what these dots look like when we stain with fluorescein. Do you see these tiny dots? I don't have a cursor to put on the dots, but I think they're probably visible, so... but these are the fluorescein dots, and, now, this is lissamine green dye which you will see as blue dots.

Can you see the blue dots over there? Okay, so these are cells that are damaged on the surface of the cornea. The transparent part of the eye, there are cells on the transparent part of the eye which are damaged, and that's why the dye is going inside, and why is that important? Because this structure, this structure of the eye is very sensitive. It has some of the densest nerve supply anywhere on the body. Any problem over here, you're going to feel it. I mean, if there's a corneal scratch, if anybody has had a corneal scratch, you know it's very painful, so anything over here is going to cause pain, and that's what's happening here, and this is when we do both things, dyes together.

11:02     Measuring the severity of ocular GVHD:  Then we put a number on how... what the symptoms are, what the complaints are, and we ask questions like do you have light sensitivity? Is there eye discomfort? Does the eye really act up in windy conditions and so on, and we give a number to each one of those answers, depending on whether they are some of the time or most of the time or all of the time, and then... and that is factored in into our classification system.

And then we look at how red the eye is, and then again we put a number and diagnose the patient as having either ocular GVHD or not. And that's important because we want to know where we start from. We want to know whether treatments are having an effect or not, and it's nice to have quantitative numbers rather than just saying, "It looks like your eye is red, irritated," but, that, you can also tell while looking in the mirror, so what are we doing?

We want to know where you start from. We want to know what the treatment effects are, and also we want to compare things across different centers, and it's nice to have something that is standardized.

12:12     GVHD is not just a typical dry eye problems:  So is GVHD another... just another dry eye? That is the number one reason why people suffer from this disease and they don't get treated very well, because there is a thought process that prevails that this is just another dry eye. If the tear production is not there, what's the difference between this and somebody who has autoimmune dry eyes, Sjogren's or just a garden-variety dry eye, or if you're working on the computer too much and the eyes are irritated, so that's another dry eye. It's the same symptoms, so just using artificial tears will be okay. That's the mistake people make.

This is not just another dry eye. This is severe inflammation of the surface of the eye due to a very profound immune attack that is being launched on the surface of the eye after a bone marrow transplant. It presents sub-acutely as opposed to chronicity that we see in dry eye. There are differences. This is one place where we see scarring on the surface of the cornea. We don't see that with Sjogren's at all or very few patients, so, if we flip the upper lid, I'll show you some pictures, we can see scarring over there which is probably pathognomonic, which is characteristic of this condition.

You don't see that in other conditions, and this is the probably with GVHD in many cases, inflammation and scarring in other organs also, so is the case with the surface of the eye, and so is this different than just another dry eye? The answer is, you bet, it is, and it has to be treated differently also. You can't think of it as just another dry eye. Otherwise, there would be a lot of suffering. The disease is going to just cause more and more problems. So what are the differences?

14:01     Mucus discharge in ocular GVHD is different than regular mucus discharge:  Here, there are mucocellular aggregates, which means the mucus that comes out. The mucus that comes out is not just mucus, it's a collection of inflammatory cells, a lot of bioactive molecules. It is an inflammatory process that we are seeing. It is not just simply mucus, so that's again something we need to understand.

14:23     Scarring under the eyelid: This is what I was talking about, the scarring that you see under the lids. That whitish area that you see on the top two slides which... That's scar. You shouldn't have that, and this is what happens in ocular GVHD and very highly diagnostic of this condition.

The lower slides show how the conjunctiva, which is the covering of the eye, how it is scarred, and now, if you pull it down, that tenting that you see, normally, you don't see that, so why? Because the fornix, the recess has become scarred and has become shallower, so all of this is happening because of scarring.

This is another thing that happens, which is that blue spot that you see on the white of the eye. That is lissamine green staining, the same blue dye, showing that under the upper lid, if you lift the upper lid on the white of the eye, there is a big patch of dryness which is extremely painful, causes a lot of pain. This is called a superior limbic keratoconjunctivitis, or SLK type of picture. Again, this needs to be taken care of.

15:36     Damage to oil-producing glands in the eyes:  Meibomian glands, they are oil glands inside the eyelids, they drop out, and sometimes there is a complete wipe out of these glands. These glands are very important because they produce oil which keeps the tears on the surface of the eye. If they are not producing oil, the tears are not going... Even if you are producing tears, they are going to evaporate. It's not going to be helpful, and so we need to replace these oil. If we don't, if you're producing it, we need to replace them. Otherwise, the surface of the eye is going to be very diseased, so there are a lot of things, as you can tell from what I'm saying, that happen, and it's not just a simple dry eye.

16:20     Damage to the eyelid:  The eyelid, there is something we call keratinization, which means that the eyelid starts taking the appearance of skin, and that's another problem that happens. And that whitish thing that you see going on in these slides, that's keratinization, and that's... Again, it can rub against the cornea and produce problems.

16:42     Damage to the cornea:  This is the cells on the surface of the eye here, are not normal, and this is something which we call... what you see in this slide is squamous metaplasia, which is also something that we can... that can happen with chronic inflammation that we see in these patients.

17:00     Non-healing epithelial defects, the surface can break down and refuses to heal for a long time till we do something specific and something aggressive to make it heal.

As you can tell, there's a lot going on here, and unless somebody is... Somebody who's experienced in these, an ophthalmologist or an optometrist, you need to have their help. You need to seek treatments that are going to prevent these things from happening, these complications from happening, but if they happen, to treat them. But how do you treat them then, so let's talk about that.

17:45     Avoid using eye drops with preservatives:  If a patient has these problems, if there is ocular GVHD and you are uncomfortable, and there are some of the things that I've shown you, they are there, we have certain general guidelines which I think are useful in planning the treatment.

The first is that you can't use preserved eye drops. Any eye drop that is preserved has benzalkonium or any other preservative, which is really a detergent which is going to be harsh, which is going to mess up the surface even more. It's starting up with the surface that has so much problem. Why would you put something that causes more problem? It doesn't make sense, so why... so we shouldn't do that. So anything that we use on the surface, it should be non-preserved.

1:34     Start first with aggressive treatment for ocular GVHD, then step down to less aggressive treatment:  Then we use a step-down approach, which means that we start with a lot of therapy, anti-inflammatory therapy and surface-healing therapy in combination so that we control the process rapidly. There is no logic to going just artificial tears, then a little bit more and, if it doesn't help, then a little bit more, then a little bit more. That's not helpful. If there is inflammation on the surface, you'll agree with me that we want to get rid of it as soon as possible, so why don't we get rid of it as soon as possible?

That's, I think, the other principle that we use is that we start a lot of treatments together and then we cut down because we want this process to be under control. We want the surface to be not under the immunological attack, and the sooner we do it, the faster we do it, the better it is. And then there is a fear of steroid eye drops and contact lenses in some practitioners, which I think is a mistake. We need to do whatever it takes to control the process and make our patients comfortable.

19:43     Treatment Options for Ocular GVHD: What are the kind of treatments we use? Preservative-free artificial tear. Now, whatever I'm going to tell you, a lot of it is... A lot of these treatments, they may be used for something else, they may be antibiotics, but they have immunomodulatory or immunosuppressive actions, and that's what we want, anti-inflammatory, immunosuppressive or immunomodulatory actions.

And sometimes, you have antibiotics, but when they are used in non-antibiotic dose, they have anti-inflammatory, immunomodulating actions, which is what we want. So I'm going to be telling you some of the treatments over here, and you say, "Why? This is an antibiotic. Why do I need antibiotic? Do I have an infection?"

No, it's not the infection. It is anti-inflammatory, immunomodulating effect of antibiotics that we want to use. So we use erythromycin eye ointment, for example, at bedtime, and the reason why we do that is because it raises the immune threshold at the threshold at which the immune reactions take place. It's an immunomodulating agent, and we want that. It's a very good way, a very good therapy.

We use doxycycline 50 milligrams once a day, and, again, the reason is that, at this dose, it has good anti-inflammatory actions on the surface of the eye, good for Meibomian glands, the oil-producing glands, and there is enough literature out there to suggest that this helps.

21:15     Compounded steroids that are preservative free:  We use compounded medications. Initially, we start with steroids which are preservative-free. They are compounded in our pharmacy, again, preservative-free because we start with doses four times a day for a week, then we taper down to three times a day, then twice a day for a week, then once a day. Once I'm at the once-a-day level, we can switch it to a commercial steroid which has preservatives because, once a day, you're not using too much preservative. That's fine, so we start off with compounded steroids to take care of inflammation.

21:53     Serum tears from blood to treat ocular GVHD:  Serum tears is a very good strategy. Serum tears is made from a patient's own blood. It's safe to use. We use it in 50% dilution and four times a day. The way we ask the patients to use it is to lay down and then use the drop, let it linger on the eye for some time, lift the upper lid a little bit so that part of it goes back in that area that... under the upper lid which is... which I showed you, which can be quite diseased.

We use them about four times a day, but you can't overdose on it. A patient can use it more often than that. It's a blood component therapy, so there is a beyond-use state that one needs to be careful about. When the bottles are thawed, they can maybe be used only for seven days; if frozen, for about 30 days or so. We have those on the instructions that we give them, but it's a good therapy.

22:49     Platelet rich growth factors (PRFG) from blood to treat ocular GVHD:  We can use the same blood that comes, which we are doing now. We can process it to make it PRGF, platelet-rich growth factor, and that has even more growth factors in it than just serum, and sometimes we can use that processed blood. So there are many things we do with blood. Platelet-rich plasma is another one we can do.

23:18     Eye drops made in a compound pharmacy to treat ocular GVHD:  Then there are some other compounded eye drops that have come out of our own work which we'll talk briefly, which are sub-anticoagulant dose of heparin eye drops, DNase eye drops or IVIG I use as eye drops. Again, all of this is designed to take care of inflammation on the surface of the eye. In combination started first so that we can control the condition, and then we move away from some of them as the response comes. These are serum tears a little bit that I spoke to you about, 50% dilution, and how you use them.

23:59     Special contact lenses to treat ocular GVHD:  Next, I'll talk a little bit about contact lenses. Contact lenses are also a very good way of making patients comfortable. It's a piece of plastic on the eye really, and that's what a contact lens is whether it's a soft lens or a large PROSE lens, but, in the end, it's a piece of plastic, and what it does is it puts the eye's surface behind this covering, and whatever is going... whatever mess is going on in the tear fluid, it's now not going to come in contact with the surface of the eye. So, if there are enzymes or molecules that are proteases or molecules that are causing problem to the surface of the eye, let it cause problem to the surface of the plastic lens because, now, the eye is under the plastic. That's one way in which it can work.

The other is that, now, the lid is not moving over a surface which is diseased, so, now the patient is going to be more comfortable because the eyelid is moving over the contact lens.

The contact lens is protecting the surface which had all this epithelial problems and was stimulating the nerves to cause pain, and so the pain and the discomfort also reduces substantially. Contact lens is a very good strategy.

We have used both soft contact lenses, type of lenses we use are silicone hydrogel contact lenses as opposed to the other soft contact lenses, and we use the larger scleral lenses also, which are the PROSE lenses, which is more of art to fit, and there are other sclera lenses also that can be used, but this is a very good strategy.

This picture, photograph shows you a contact lens on the surface of the eyes. Look at the edge of the contact lens. You can tell very well that the contact lens is placed in the first picture. In the second picture, where you see lissamine green staining, see where the contact lens was covering? Their blue dots are so few, but, outside that area, they become very dense. Why? Because the contact lens is protecting that surface, and that's what we want.

26:14     In the picture that is at the bottom, you see that rim, that white rim, why is that white rim over there? Because we had a soft contact lens on the eye, and that's the area where the contact lens was placed, that edge of the contact lens, and that area does not have those blue dots. Outside that area, a lot of blue dots, right. So... and then you say, "Why don't we go bigger then?" Of course, that's why we go for the PROSE lens, which is bigger. Can we go bigger? I don't know. Maybe we can, but we don't probably have those contact lenses, but that's the idea, that we cover the surface of the eye, prevent it from all the mess that is... inflammatory mess that is going on in their tear fluid, protect the surface from the lids and make the patients more comfortable and their disease less. Contact lens is a very good strategy.

27:05     Emerging Treatments for ocular GVHD:  Are there any new treatments? We have done a lot of work on what goes on on the surface of the eye and in the tear fluid, and we found that there are a lot of inflammatory material that is produced from cells which are called neutrophils, and we published a lot on these. But the bottom line is that these neutrophils that produce this inflammatory mess, which we call neutrophil extracellular traps, they can stimulate... They cannot just directly cause cytotoxicity or pathology on the surface of the eye, but also can stimulate autoimmune reactions that can further add to the injury, and we have this diagram which shows... and, after the presentation, I can talk and explain this more. This will take probably four hours, not 40 minutes, so we'll just move on.

But the reason why I'm showing this diagram is that there are many new therapies that we are developing that can help counteract the bad effects of these molecules at various places.

28:32     Brimonidine nanoemulsion: One of them is brimonidine nanoemulsion that came from our lab, but is now being taken to phase three clinical trials, and I think Ocugen has a stall outside where they talk about their clinical trial. It's an ongoing clinical trial. They're still recruiting, and this is something that we believe can help patients with ocular GVHD.

28:51     Other eye drop options for ocular GVHD:  There are other clinical trials that are going on, again, that came from our lab. One of them is to use DNase eye drops, which cuts the backbone of these inflammatory strands, and that's... that we are very excited about. Intravenous immunoglobulins used as eye drops is another one that we are using now which works very well. We've done one phase, one clinical trial on it, and, actually, just the paper was published two days ago, and so people are now talking about it. So there are many new therapies that we are developing, DNase, heparin, brimonidine nanoemulsion, IVIG eye drop. Cambium is another company which is developing a platelet cell lysate, which is also in clinical trials.

There's a lot going on in the field, but for these kind of therapies, one either has to be in clinical trials or have to use them off label. Whichever way, you have to go to a center that is really doing these treatments, but there's a... but my point in bringing this up is that there is a lot that is going on, and we are figuring things out on why ocular GVHD happens at the molecular level, at the cellular level, and there are new treatments in the works. You can get them even now as part of clinical trials or as... in centers which are giving them.

30:29     These are just data about brimonidine nanoemulsion, which folks from Ocugen outside can talk to you about. This paper is published now. I took this collage from the paper. This shows how, when we use IVIG as eye drops, it reduces surface disease as compared to eye drops that don't have IVIG, which is basically... What is IVIG? These are basically antibodies that are pulled from thousands of volunteers, donors, and these antibodies are concentrated, and then we use these antibodies to treat the surface, and it's pretty, they have great anti-inflammatory, immunosuppressive, immunomodulatory effects. This is something that we are very excited about.

31:02   Does ocular GVHD cause blindness?  "Will I go blind from this disease," and I'll stop now in a few minutes, the answer is no, but it can affect the quality of life. This is a statement that one of our patients from Seattle told me on the phone. It was relayed by the physician who was referring the patient, that the patient is...

The person who was suffering from ocular GVHD described the symptoms as eyes have been dipped in hot sauce and rolled in sand, and that probably is the way to describe this. This could be very painful. The vision can go down because of the surface disease. There could be secondary problems like herpes simplex infection on the cornea that can cause problems, so which could be vision-threatening. There could be bacterial infections that can happen that can be vision-threatening, but, in general, it does not... It's a quality-of-life issue. Yes, there can be some vision-threatening problems, but treated fine, if you're having regular follow-ups, it's not going to rob you of the vision.

32:30     These slides show how we work and the ocular GVHD meeting, and I think we'll take question and answers from here on.

32:43 [Moderator] We'd like to thank Dr. Jain for his presentation, and now we'll open the floor up for questions.

32:52 [Audience] Demodicosis and  blephartitis: How much blepharitis is caused by demodex or dry eye? It's nasty. How much do you see demodicosis in stem cell patients? Did I get that right?

[Jain] Yeah, so the question is that, in the eyelid margin, there are eyelashes and, at the base of eyelashes, there are commensals. Commensals means things that stay with the human body like bacteria. We have more bacterial cells, by the way, than human cells. I hope you know that. We are a covered with bacteria, and so these are organisms that reside in the base of eyelashes called demodex. The issue is are these the reason for ocular GVHD? Do they contribute to ocular GVHD or blepharitis or symptoms that the patients are having?

It's a controversial question. It's a controversy in general also how much demodex causes problems. But my view is that, in ocular GVHD, demodex would probably cause the same problems as they would in patients who do not have ocular GVHD, meaning, they may be a little bit of a nuisance or they're causing some blepharitis, but that's not the reason why a person has ocular GVHD. Ocular GVHD is an immunological attack after the bone marrow transplant on the surface of the eye. That's what it is, so how much would demodex contribute? One can pull their lashes to see if they are there, and then one can treat them. They could be contributing a little bit more to the symptoms, but they are not the reason for ocular GVHD.

[Moderator] There's a question over here.

34:48 [Audience] Treatments cost concerns:  Hi. I am very concerned about the expense. I now am using myself the serum, and it really does help, but I can't afford to keep on using it. Is there any help in that area?

35:07 [Jain] Yeah. Serum tears is compounded, and any compounded medication, unfortunately, is not covered by insurance because of its off-label use. I wish people were doing clinical studies and trials and getting them to be FDA-approved and... but that's just a wish.

The costs differ. At our institute, the only cost that is placed on the patient is the cost of making them, and that's... At UIC, they charge $85 for a 30-day supply, and then you might wonder why 30-day supply? Why one week? Why don't we say you can use it for three months or you can use it, although most patients end up doing that, but the reason is that there are regulations, and there is something called beyond-use date, which is mandated by the federal government, and that's what the pharmacists tell you, that once you freeze them, you can use them for 30 days. Once you thaw them, you can use them for seven days.

36:18 [Jain] The answer to your second part of your question, "Is there help?" In many small ways at UIC, we try to help people with a small fund that we have called the GVHD Fund, which we established about two years ago, and patients who have really, really nasty surface problem and they really can't do anything about it, we cover their cost at least for the initial treatments, and, obviously, we can't, we don't have very deep pockets to cover them for the whole year or so. We would like to if there are more donations that come into that fund, but we try to help as much as we can, but I do understand this is a very important issue. How do you cover this cost, and this is just serum tears. There could be other off-label treatments also that we give, so it all adds up.

37:09 [Audience] Last year, I was able to go to MAP, and they helped me pay for my drops. They're right down the street from UIC. You just have to fill out a form, and they'll approve it. It's Medical Assistance Program, and they're really helpful.

37:27 [Jain] That's good to know for me also. Yeah, it's called the Medical Assistant, and, also, I was told from the VA you get them much cheaper. There's someone over here also who's from the VA.

[Moderator] We have a question back here.

 [Audience] Two questions, who sponsors MAP?

[Jain] It's UIC.

37:53 [Audience] Trying new treatments: It's UIC? Okay. Thank you. Okay, my question for Dr. Jain is, if you've had ocular GVHD for a while, to what extent would any of the new treatments be helpful?

38:09 [Jain] Can you repeat the question please?

 [Audience] Yes, if you've had ocular GVHD for five years, to what extent might any of the new treatments be helpful for a patient that scores zero on the Schirmer test and is currently in one of the hard contact lenses?

[Jain] The question is that, and it's a good question, the question is that if you have ocular GVHD and now you're five years out, would the new treatments help or how do we think about this?

Ocular GVHD, when it develops, I have been saying this over and over again that this is a immunological attack from... that goes on the surface on the eye. That happens within the first two years or so. After that, it tends to burn out. So, if you divide the disease in two phases, the first phase, it's causing the damage, and if it causes the lacrimal glands to shut out or the surface to become messy, but that is immunological attack, and we do all these kind of treatments to take care of it.

After it has died down, it has left in its wake the damage. That hasn't gone away.   So, although there is no new immunological attack on the surface of the eye, but the eye now at five years has lost the ability to produce tears and, if the Meibomian glands are not there, it's not producing oil, so it has become a severe tear-deficient dry eye, which in of itself starts getting into a vicious cycle of inflammation even without ocular GVHD bases being active, so would these treatments and newer treatments that we are saying, would they help?

The answer is, yes, they would because the inflammatory cycle now is being sustained by different mechanisms, but still it's an inflammatory cycle, perhaps not the ocular GVHD inflammation, but dry eye inflammation. Does that make sense? We are talking about two... We transition from ocular GVHD being the driver of all the problems to dry eye, tear-deficient dry eye being the drive of the problems.

40:22 [Audience] Changes in Pupil Size: My wife has been treated for GVHD eye for a couple of years actually with quite a bit of success, but she has unequal pupil size periodically. Sometimes, the left is visibly larger, sometimes, the right. They've done CAT scans and MRIs and Dopplers, and they say, "We have no idea what's going on." Is that from the GVHD?

 [Jain] Unlikely. My experience has been that GVHD, for the most part, if not all, is an ocular surface disease. It does not affect the internal structures of the eye, so the pupil could be related to... and I'm sure they went to the entire neurological examination to look at the various reasons for the pupils to be unequal, but that seems to be a unrelated issue. Very rarely would ocular GVHD cause any problems inside the eye.

 [Audience] Hello. First of all, I want to thank Dr. Jain for helping my wife get a better quality of life, and, Dr. Nathan is it?

[Nathan] Yes.

41:44 [Audience] Relationship between cataracts and ocular GVHD:  I think you may just have answered it, but my question was, my wife had ocular GVHD, can it come back, and the second question is how do cataracts correspond or affect or come into play with ocular GVHD?

[Nathan] As Dr. Jain already touched upon that, the ocular GVHD has a lifespan. After two years, it's on the surface. It's taken care of, but whatever longstanding side effects come because of the extent to which the ocular GVHD affected the eye, that then later on starts causing trouble.

42:24 [Nathan] As far as developing cataracts go, it's not a direct effect of the ocular GVHD per se, but it's the treatments that you get for it, and most commonly, whenever somebody does develop ocular GVHD, since very rarely it occurs on its own, you may have other sites that may be involved, we do start patients on systemic steroids, and those systemic steroids, meaning, prednisone that you may have heard about, which everybody dreads and... but in the initial phase, the combination treatment helps control the inflammation and helps to... helps simultaneously with the topical treatment, but it is those steroids, when you use it for an extended period of time, that can affect the lens and lead to the cataracts.

43:17 [Jain] That's what we see, cataracts, because just the fact that the patients were on steroids. Cataract surgery in ocular GVHD is also pretty successful. It's not a problem. The results that we have seen are comparable to what we see in general patients who have cataracts. There are some issues, for sure. The issues are that the recovery time may be longer. There could be more discomfort in the recovery phase. The surface epithelium may slough off and we have to put a contact lens. We like to put a suture in the wound so that, if we go to a contact lens earlier, we don't distort the wound, and so there are some differences.

[Jain] There's some eye drops that we don't like to use after a cataract surgery in ocular GVHD patients. These are nonsteroidal anti-inflammatory drops, ketorolac or Acular, because they can cause corneal melts and problems, so you... they... if done fine, if we know what we are going for, the overall picture, if we know that this is ocular GVHD and we have to do certain things a little bit differently than normal cataract patients, then the outcomes are the same, no difference. They are very happy.

44:40 [Audience] When should doxycycline be used for ocular GVHD?  Hi. A couple of questions just quickly with regards to folks with advanced GVHD who have lost their Meibomian and lacrimal glands. Is doxycycline still a worthwhile PO to try or, again, is it too far advanced?

[Jain] Doxycycline, I mean, obviously, it's best if there is something to save. If there's nothing left to save, it's... then there's nothing out there, but doxycycline still has good anti-inflammatory effects on the surface of the eye. We'd still go with it.

But, on the subject of Meibomian glands, I... We like to blame ocular GVHD for it, and our experience now, our position is changing on that, that a lot of... In a lot of patients, these glands are already lost before they got their bone marrow transplant because of the chemotherapies they were on. So you did enter the bone marrow transplant with not even having those glands in the first place. The chemotherapies are the one to blame for that, and we are seeing that in a lot of our patients.

We haven't seen a whole lot of progression in Meibomian gland dropouts with patients who have even full-blown ocular GVHD, so I don't know how much ocular GVHD is really killing those glands, or maybe we are protecting them with the things we are doing and we're not seeing what would ordinarily happen if we were not giving those treatments, so it's hard to tell.

46:11 [Audience] LipiFlow:  Interesting. Excuse me. Are you familiar with something called LipiFlow? It's a technique that I've recently learned about, and, again, I'm wondering if it's any good in people without tear glands and Meibomian glands and in advanced state?

[Jain] I'm fond of calling LipiFlow as the spa version of warm compresses and we can have good music and some... playing, and it's just an $800 treatment. I don't think there is any harm in it, but I think, if you are doing warm compresses and lid scrubs, so warm compresses mainly every day, the idea is the same, that you want to increase with heat, you want to increase the temperature, and with a little pressure on the surface of the eye, you want to drive the oils out, and while you are doing that, if you do that every day, you may not need the same pressure as with LipiFlow, but if you have the $800 and you don't mind spending them, I would say go for it.

47:12 [Audience] Redness in eyes without pain:  Yes. Thanks, Dr. Jain, for your presentation. I'm 18 months post-transplant. My oncologist, when I come in, he looks at my eyes. He said, "Do they hurt? Are they scratchy? Do they itch?" No. No. No, but, every once in a while, I look in the mirror and I see redness on the side, and my wife gets concerned about it, but I'm not having any ocular pain or discomfort, so my question is would a regular ophthalmologist be able to treat me for this condition, because I don't know that my oncologist would know an ophthalmologist who specializes in this, so that's the question. How comfortable could I be going to a regular ophthalmologist with a condition like this should it occur?

48:10 [Jain] Pain is not a good indicator of the health of your eye surface:  When we treat ocular surface diseases in general, there is a very well-known disconnect between... in a lot of patients between what they perceive as discomfort because of their eye disease and the extent of eye disease. They're not as congruent as we... If it were it will be easy, but they're not, so you could have a situation where you have a lot of eye disease on the surface, but you are happy and you're not complaining at all, and, on the other side of the spectrum, are patients, we look at the eye and say, "There's nothing I can find," but they're very, very symptomatic, so pain and symptoms are not a true indicator of what's going on on the surface. That's number one, very important to understand, and that's why I began this presentation by saying that, if there is anything that goes on with the eye, any light sensitivity, any mucus discharge, any redness, you need to seek an examination from someone who knows about it right away.

Now, that examination itself, now what would the person who's examining do? If they're just going to look at your eye and say the same thing, "Your eyes look a little red. Use artificial tears," that's not helpful, so one has to know whether there is inflammation going on. Are there tests that can be done? The answer is yes. There is an inflammatory dry test, MMP-9 test, which we use very often, and it can show a pink line like a pregnancy test that shows pink lines and tell you that you have an ongoing active inflammation on the surface of the eye.

I think it is important that you tell your oncologist that you would want to go to ophthalmologist at places which deal with this condition, and I think it is very important to educate them also because I would... and we are trying to do so ourselves in that this is not just another dry eye situation, and that's the message, that... If there's one message that I want to give everybody here and you want to transmit to your oncologist is that this is not just another dry eye. Please don't think of it that way. This is more serious than that. This requires an examination tailored to that and treatments that are different and that are more aggressive perhaps than what you would do in just another dry eye.

Restasis and Xiidra, they are prescription medications, they are given, but they may not and do not work in this situation, so let's not just have false comfort.

50:49 [Nathan] Yes, and I would like to second that. In all of our patients, we work very closely with Dr. Jain and his group, and we are actually now trying to even send patients before they go to a transplant to get their eyes evaluated, and then we have them follow routinely whether you have symptoms or not. It is good to know that you're okay.

I mean, we go to the extent of even having a referral, just a follow-up visit even if he doesn't ask for it. We do send them if somebody is coming off of their immunosuppression because that's the time you may see that inflammation can act up and can run you into trouble So we really don't take it very lightly and, as Dr. Jain also mentioned, it needs to be a combined treatment that needs to be done. And we looked at this, and there was a consensus group between the two transplant groups, Europe and in the US, and I was a part of that, and the main thing we take off whenever you think about ocular symptoms is work with an ophthalmologist who knows what they're doing. Very, very important.

51:57 [Audience] Light Sensitivity:  Hi. My name is Bridget. I'm here with my daughter, Nikki, who is five years transplant. She has the light sensitivity, still has it to this day. We've tried the lenses, the eyeglasses. I mean, is there anything?

[Jain] Light sensitivity, one obviously has to see what could be the reason for light sensitivity. Is the reason for light sensitivity, is that the surface has a lot of dry cells on it so that when the light hits it irritates the nerves, and if that's the reason, one has to take care of that. Or if the reason that there is maybe a cataract that has developed which... so when the light enters the eye, it deflects and, instead of forming a clean image on the retina, it's now dazzling the retina.

There are reasons for light sensitivity to be there, and one has to work to exclude each one of them and, once you figure out which one it is, then, of course, you target that reason. But I think light sensitivity is something that is addressable because it seems that, in a lot of patients, we are able to figure out what could be the reason that is contributing to it.

 [Moderator] I think we have time for one more question. We're going to get somebody who hasn't... I think... Did you have a question?

53:33 [Audience] Loss of Vision: Yeah. Karen is... I'm her caregiver, and she's 24 years out of her bone marrow transplant, and so, now, she has lost vision in her right eye, and they're... Her ophthalmologist is only treating her for severe dry eye. She's not gone to any of the medication., And we're wondering if... She's wondering if the damage is permanent because she has now a limited vision in her right eye.

[Jain] We, obviously, need a little bit more information than that, that whether the loss of vision was due to the surface of the eye becoming scarred or opaque, the transparent part of the eye, the cornea being scarred such that it is not allowing light to go in, is that the reason, because of dryness and so on. Or is the reason to do with the retina or something else going inside? What is the reason why the vision has become the way it is?

54:52 [Jain] There are many reasons why the eye could lose vision. One person could have high pressure and glaucoma, which can basically kill all the nerve fibers, of the nerves to form vision. There could be problems in the retina that can cause her vision to be lost, there could be... the front of the eye. Now, if it's the front of the eye, then those are addressable. There are surgeries than help. Again, this would be something that one needs to look at to see whether it is a front-of-the-eye, addressable, surgically addressable cause or whether it is a back-of-the-eye reason for the vision to be lost. That's why I said we probably need more information than that to address that question in a more meaningful way.

 [Moderator] In the interest of time, we're going to thank Dr. Jain and Dr. Nathan for their expertise and time this morning. This will conclude the morning session, and you are free to move on to the next morning session.